To fulfill its role of protecting the deep, sensitive, gas exchanging alveolar regions, the mucociliary system responds via the interaction of both neural and humoral pathways activated by unnatural environments in either central or peripheral regions of the lungs. Irritant, toxic or pathogenic challenges may result in defensive responses designed to maintain pulmonary homeostasis, or they may result in responses that lead to impaired mucociliary function, with its consequent effects on gas exchange. The agents to be studied, capsaicin, sulfur dioxide, oxygen and Ascaris suum antigen, mediate their effects on the mucociliary transport system through a number of pathways and mechanisms, including sympathetic, parasympathetic, cyclooxygenase, and the release of intracellular mediators, depending both on the agent involved and the site of insult. The test agents were chosen to investigate both the diversity of pathways whereby mucociliary transport is regulated and the contrasting effects that each of these agents is predicted to have on mucociliary clearance. Using this approach, we will formulate a more comprehensive model of the pathways and physiological consequences of the mucociliary system's response to irritants. To accomplish this we will use the following in vivo canine assays developed in this laboratory: ciliary beat frequency (CBF), tracheal mucus velocity (TKV), bronchial mucociliary clearance (BMC) and lower airway glycoprotein output (IAGO). To evaluate the importance of these parameters in maintaining effective mucociliary transport, we will use data from these in vivo studies combined with rheological data derived by magnetic rheometry and from in vitro CBF studies of the effects of agents on the characteristics of the metachronal wave to develop models of the mucociliary transport system. It is by understanding these pathways and mechanisms that the significance of the role of the mucociliary transport system and its components in pulmonary homeostasis can be determined, abnormalities in its response can be defined, and scientific rationales for therapeutic interventions of impaired function can be developed.